JPH08503962A - Novel N, N, N ', N'-tetra-substituted-1,2-ethanediamine derivative compound - Google Patents

Abstract

PCT No. PCT/EP94/02363 Sec. 371 Date Apr. 21, 1995 Sec. 102(e) Date Apr. 21, 1995 PCT Filed Jul. 18, 1994 PCT Pub. No. WO95/03270 PCT Pub. Date Feb. 2, 1995The invention relates to new N,N,N'N'-tetra-substituted-1,2-ethanediamine compounds of the general formula (I): <IMAGE> (I) wherein X is a carbonyl (CO), hydroxymethylen (CHOH) or p-fluorophenyl-methylen (p-F-C6H4-CH) group and R is a benzyl group optionally substituted in p- with an halogen, or R is a 2-pyrimidinyl group with the proviso that simultaneously X may not be p-fluorophenyl-methylen (p-F-C6H4-CH) and R may not be an unsubstituted benzyl group, as well as their pharmaceutically acceptable additions salts. The compounds are potentially useful in the treatment of sigma receptor-related nervous system diseases.

Description

Detailed Description of the Invention   Novel N, N, N ', N'-tetra-substituted-1,2-ethanediamine derivative compound Description of the invention   The present invention has the general formula (I): [In the formula, X is carbonyl (CO), hydroxymethylene (CHOH) or p- Fluorophenyl-methylene (p-F-C₆H_Four-CH) group, and R is halo at p-position A benzyl group optionally substituted with gen, or R is 2-pyrimidinyl It is the basis. However, at the same time, X is p-fluorophenyl-methylene (p-F-C₆H_Four -CH) and R is not an unsubstituted benzyl group] new N, N, N ', N' -Tetra-substituted-1,2-ethanediamine compounds, and their pharmaceutically acceptable Related to added salts.   In the compound of the general formula (I), the benzyl group may be substituted at the p-position. Rogen is preferably fluorine. Among the pharmaceutically acceptable salts, the hydrochloride and And sulfate are preferred.   The compound of the present invention is obtained according to the following reaction formula.                                 Reaction formula 1   In fact, the general formula (II) of N, N'-dimethyl-1,2-ethanediamine [where Y is Chlorine or bromine, where R is as defined in (I)] Alkylation with the general formula (III) [wherein R is as defined in (I) The intermediate of [A] is induced. Applicants have used chlorinated compounds (II, Y = Cl) Was found to be advantageous for the alkylation reaction. Ie used for this reaction Preferred compounds of general formula (II) include benzyl chloride, p-fluorobenzyl Chlorides, 2-chloropyrimidine and the like are included.   2- (4-fluorophenyl) -2- (3-halopropyl)-of the intermediate of general formula (III) 1,3-dioxolane (IVa) (wherein Z is preferably chlorine) Subsequent alkylation leads to the derivatization of the intermediate of general formula (V), 1,3-dioxolane The body is guided. This reaction is carried out in the presence of a base that reacts with the hydrogen acid formed. Is advantageous. Applicants have found that inorganic bases such as carbonates and bicarbonates, We have found that potassium carbonate is extremely suitable for this reaction. Add reaction progress It is also advantageous to add a catalytic amount of potassium iodide for speeding up. Usually a reaction An inert solvent such as acetonitrile is recommended as the medium. The reaction is under heating At the boiling point of the mixture.   By acid hydrolysis of 1,3-dioxolane (V), the general formula (I) of the present invention is obtained. And X is carbonyl (CO) and R is the final compound as defined above. It is done. This reaction is preferably carried out with water and an alcohol containing up to 4 carbon atoms. Advantageously carried out in a hydroalcoholic medium, preferably including a mixture of ethanol It is done. Mineral acids such as hydrochloric acid, hydrobromic acid, etc. are selected as the most preferred acids ．   The compound (I, X = CO) obtained as described in the previous paragraph was reduced Therefore, in the general formula (I), X is hydroxymethylene (CHOH) and R is Provide the final compound as defined. This reduction is a reducing agent such as hydride For example, using sodium borohydride, an anhydrous alcoholic medium such as anhydrous ethanol is used. It is advantageous to do this in a tanol.   Unlike the final product (I) where X is a carbonyl group (CO), X is p-full Orophenyl-methylene (p-F-C₆H_FourThe final product (I) which is Obtained from the intermediate of formula (III) by a one-step reaction. This reaction is 1,1'- A selected from (4-halobutylidene) bis (4-fluorobenzene) (IVb). It is carried out by a rukilling agent. This alkylation is performed by (IVa) Substantially the same as the reaction and is performed in the presence of the same auxiliary agent and solvent. (IVb) In, the Z halogen atom has the same properties as in (IVa).   U.S. Pat. No. 4,588,728 describes cis-9- [3- (3,5-dimethylpipera). Treatment of psychosis with dinyl) propyl] carbazole has been described. US Patent No. 4,709,094 describes the production of 1,3-disubstituted guanidines and Can be used in the diagnosis and treatment of hallucinations associated with mental disorders and chronic psychotic depression. Has been described. U.S. Pat. No. 4,929,734 describes N-substituted 1- (1,2,3 , 6-Tetrahydro-3-pyridinyl) oxime and N-substituted 1- (1,2,3,6- Production of tetrahydro-4-pyridinyl) oxime and their depression and psychosis And / or use in the treatment of inflammatory diseases. US Patent No. 5 , 061,728 includes 4-phenyl-1,2,3,4-tetrahydro-1-naphtha. Use of renamine derivatives in the treatment of psychosis and inflammation and their immunity Its use as an inhibitor is described. US Pat. No. 5,086,054 Production of arylcycloalkylpolyalkyl-amines and their antipsychotics Use as medicine, ischemia treatment, stroke treatment, anti-dementia drug and anticonvulsant Has been done. U.S. Pat. No. 5,162,341 discloses amphetamines and related compounds. The use of various compounds for the treatment of addiction to drugs has been described. US Patent No. 5,175,174 describes the preparation of N-phenyl-piperidyl-4-amine derivatives. And their class III antiarrhythmic agents, potassium channel blockers, antipsychotics , And its use as an anticonvulsant and neuroprotective agent. US Patent No. 5 , 158, 947, the production of N-piperidyl-alkyl-benzazepine derivatives Structure and their use for the treatment of neuropsychiatric disorders. US Patent No. 5,116,995 describes the preparation of 4- (aminoalkyl) carbazole and its preparation. Their use as antipsychotics has been described. US Pat. No. 5,149,81 No. 7 includes the production of 4-phenyl- and 4-thienyl-tetrahydropyridine and Their use for the treatment of depression, psoriasis, schizophrenia and cerebral ischemia is described. ing. U.S. Pat. No. 5,109,002 describes a 1-system Chloalkyl-piperidine derivatives and their antipsychotics and diss Its use for the treatment of kinesia is described.   The compounds disclosed in all of these patents are for sigma (σ) receptor in the nervous system. It is common in that it has affinity as a ligand for the body. In this regard , B. L. Largent et al. (Eur. J. Pharmacol.,155, 34 5-7, 1988), S.M. I. Deutsch et al. (Clinical Neuro opharmacology,11(2), 105-119, 1988), T.S. P. Su (Eur. J. Biochem.,200, 633-642, 1991). Review article describes biochemical, pharmacological and clinical aspects of sigma receptor ligands Has been done.   Applicants have found that the compounds of the present invention are chemically significantly Shows high affinity as a ligand for sigma receptors, despite differences I found that. Due to such activity, the compounds of the present invention are May be useful for the treatment of receptor-related mental disorders, primarily psychosis and schizophrenia Potential is considered.   Furthermore, from the patent literature, it has several N-atom substitutions, the substituents being of the general formula (I) 1,2-ethanediamine derivative compound structurally similar to that of Are known. For example, French Patent No. 2,279,383 describes another compound. Especially N-benzyl-N '-(4,4-bis- (4-fluorophenyl) butyl) -N, N'-dimethyl-1,2-ethanediamine is disclosed and is the compound of Example 9 of the present invention. The difference between and is only the presence of a fluorine atom at the p-position of the benzyl group. However, above N-benzyl-N '-(4,4-bis- (4-fluorophenyl) in the French patent Butyl) -N, N'-dimethyl-1,2-ethanediamine has cardiovascular activity It is just an intermediate used to obtain compound. Similarly, US Pat. No. 4,645 has sedative, anti-emetic and gastric ulcer inhibitory effects, and Belonging to a group of compounds reportedly useful as central nervous system stimulants 4- Amino-3,5-dibromo-α- [3-[[2- (diethylamino) ethyl] amino] propyi ]]-4'-Fluorobenzhydrol is disclosed. This compound is a structural example It is quite similar to compounds 6, 8 and 9. Similarly, In European Patent No. 511,072, in particular, α₁-For adrenergic receptors With antagonistic activity and α in the lower ureter₁-Adrenergic Treatment of arousal disorders, especially benign prostatic hypertrophy, dysuria and polyuria 2-[[2-[[3- (4-fluoropheno), which belongs to a group of compounds that may be useful for Xy) propyl] methylamino] ethyl] amino] -4-pyrimidine-caboxyamide It is disclosed. This compound is structurally rather similar to the compounds of Examples 12 and 13. are doing.   Structural similarities between compounds of general formula (I) and the abovementioned compounds described in the patent literature Despite the fact that the compounds of general formula (I) are surprisingly Can bind to the body and thus be useful in the treatment of sigma receptor-related diseases I found that there is a property. Haloperidol is σ and D₂Both of the receptors It is widely used as an antipsychotic drug for the treatment of humans (BL Largen). t et al., Eur. J. Pharmacol.,155, 345-7, 1988). This On the contrary, the compounds of the present invention have the following major advantages over haloperidol:₂Receiving Shows a higher selectivity for the σ receptor than the receptor and therefore D₂Mutual interaction with the receptor It is unlikely that the effect exerts an effect on the extrapyramidal system (Table 1). The results in Table 1 are , Binding to σ receptor is stronger than haloperidol, and D₂Acceptance Due to its low activity on the body, the preferred compound of the present invention is 1- (p-fluorophenyl). Phenyl) -4- [N- (2- (N '-(p-fluorobenzyl) -N'-methyl-amino) ethyl)- N-methylamino] -1-butanone dihydrochloride (I, X: CO, R: p-F-C₆H_Four-C H, 2HCl, Example 7). Furthermore, side effects of the compound of Example 7 The lower expression rate of haloperidol was compared to the stereotyped behavioral inhibition test (Table 2) and Have been proved by the Irvine test (Table 3).   σ and D₂Specific binding to the receptor was tested as follows.   σ receptor: Radioactive 3-PPP ((+) [acting as a specific ligand³H] 3- [3- A 2-nM solution of hydroxyphenyl] -N- (1-propyl) -piperidine) was added to Tris Membrane equivalent to 40 mg of whole guinea pig brain buffered to pH 8.5 with hydrochloride and 25 ° C And incubated for 90 minutes. Thus, the total binding of the ligand to the membrane was gotten. Then, by adding micromolar concentration of unlabeled 3-PPP, Heterologous binding was measured. Obtained by adding the compounds to be tested at 11 different concentrations IC from the inhibition rate of specific binding₅₀The value (50% inhibitory concentration) was calculated. Incubate After completion of the procedure, the sample is filtered through a glass fiber filter and then Tris. It was washed 3 times with a hydrochloride buffer. The amount of radioactivity bound to the receptor is maintained on the membrane and It was measured by a body scintillation counter.   D ₂ receptor: Radioactive spiperone ([[which acts as a specific ligand³H] Spipero Striatum 20 buffered with Tris-hydrochloride to pH 7.4. Incubated with a membrane corresponding to mg for 20 minutes at 35 ° C. Then, Micromo The non-specific binding was measured by adding unlabeled spiperone at a concentration of 1%. Compound to be tested From the inhibition rate of the specific binding obtained by adding 11 different concentrations₅₀(50% The inhibitory concentration) was calculated. After the incubation was completed, the sample was It was filtered through a filter and then washed 3 times with Tris-hydrochloride buffer. Bound to the receptor The combined radioactivity was maintained on the membrane and measured by a liquid scintillation counter. Was fixed.   Stereotyped behavior prevention test: Male Sprague Dawley rats weighing 200-300 g used. Animals were weighed and placed in individual clear boxes. Test at time 0 Compound was administered intraperitoneally. As a vehicle, 0.25% agar was used. After 30 minutes, apomorphine at a concentration of 0.6 mg / ml was administered at a dose of 1.5 mg / kg. Subcutaneously. At 40, 50, 60, 90 and 120 minutes, stereotyped behavior It was scored from (-) to (+++) according to the following criteria. That is, (-) stereotyped No behavior and any abnormal movements; (+) slight stereotypic behavior of hands and intermittent Sniffing (sniffing behavior); (++) intense hand movements, sometimes sniffing Mild licking (licking behavior) with gutting; and (+++) strength licking And / or knowing. The result is the amount required to improve the numerical value , Mg / kg ED₅₀Express as.   Irwin test: This test is for completely unknown properties of compounds Each set consists of a set of tests intended to find the degree of its nature. Evaluation Begins with whole body observation and progresses in stages to more detailed observation. Changes in control animals Scored arbitrarily from the observation of.   The following parameters were evaluated based on the behavior of animals.   a) General examination: gender, weight, age, etc.   b) Behavioral tests: Agility, locomotor activity, mood.   c) Neurological examination: central nervous system, autonomic nervous system, posture, ataxia, muscle tonus, Reflexes and systemic signs.   Results were expressed as the first dose that produced undesirable behavioral and neurological effects ． Σ and D expressed in nanomolar concentration (nM) under the described conditions₂To the receptor IC₅₀The values are shown in Table 1. This table also shows the selectivity D₂/ Σ ratio and halo R of relative selectivity for Ridol₂The / σ ratio is also listed. That is, the preferred compound Things are selective D₂It is a compound with a high / σ ratio. Haloperidol has the lowest selectivity Yes.   ED in Table 2₅₀Results of stereotypic behavior expressed as (mg / kg) Compound, 1- (p-fluorophenyl) -4- [N- (2- (N '-(p-fluorobenzyl) -N' -Methylamino) ethyl) -N-methylamino] -1-butanone dihydrochloride ED₅₀But halo It shows that it was 80 times larger than that of peridol. This is a new compound Is D₂Much weaker as an inducer of unwanted receptor-induced abnormal behavior I'm telling you. This finding also agrees with the biochemical results shown in Table 1.   Furthermore, the results of the Irvine test (Table 3) show that 1- (p-fluorophenyl) -4- [N- (2- (N '-(p-fluorobenzyl) -N'-methylamino) ethyl) -N-methylamino] -10-fold higher dose of 1-butanone dihydrochloride than haloperidol It shows that no undesirable effects were observed until reaching. New compound Unlike haloperidol, it does not cause catalepsy, which is its major cure. This is a medical advantage.   The experimental results obtained show that the compounds of the present invention are associated with nervous system diseases related to sigma receptors, especially Anoxia, anxiety, convulsions, dyskinesia, drug addiction, schizophrenia, hypoxia Suggests that it may be useful for treatment of dementia, cerebral ischemia, dryness, psychosis and stress There is. The compounds of the invention may be combined with a suitable vehicle to provide oral, rectal or parenteral administration. It can be administered by the route. These compounds are 0.5 to 100 mg daily, and It is preferably administered at a dose in the range of 1 to 30 mg daily.   Example 1-1-benzyl-1,4-dimethylethylenediamine   N, N'-Dimethyl-ethylenediamine (88.15 g, 1 mol) in anhydrous ethanol It was dissolved in water (300 ml). Then, NaHCO₃(252 g, 3 mol), Benzyl chloride (126.5g, 1mol) and ethanol to a volume of 1L I added until. The mixture was refluxed for 20 hours and then cooled. The inorganic salt is filtered and The body is washed with a small volume of ethanol and the liquid phase is completely depleted of ethanol. It was evaporated until Pure product is high vacuum distillation (pressure: 01mmHg, distillation temperature : (58-60 ° C.) in the form of a bright clear colorless oil. yield: 51.1%.   Example 2: 1,4-dimethyl-1- (p-fluorobenzyl) ethylenediamine   Similar to Example 1, using 4-fluorobenzyl chloride as the starting material , 1,4-Dimethyl-1- (p-fluorobenzyl) ethylenediamine was obtained. Distillation temperature: 66 to 67 ° C./0.01 mmHg. Yield: 57.6%.   Example 3: 4- [N- (2- (N'-benzyl, N'-methylamino) ethyl) -N-methylami No] -1- (p-fluorophenyl) -1-butanone ethylene ketal dihydrochloride   1-benzyl-1,4-dimethylethylenediamine (35.6 g, 0.2 mol) , Γ-chloro-p-fluorobutyrophenone-ethylene ketal (58.7 g, 0. 24 mol), anhydrous K₂CO₃(82.8 g, 0.6 mol) and a catalytic amount of KI Stir the mixture in cetonitrile (500 ml) and heat to reflux for 24 hours to react Is the TLC (Cl₃CH-MeOH, 9: 1; Silica gel F₂₅₄) I ran. The resulting solution is left to stand at an appropriate temperature, the inorganic salt is filtered, and the rotavapor is used. The solvent was evaporated using. Purify the resulting liquid by chromatography ( Rica gel; Cl₃CH: MeOH, 9: 1). Pure production by TLC The fractions showing the presence of product were combined and the solvent was evaporated, yielding 32.0 g (product yield). (50.5%) in the form of a bright oil, which is used directly in the following steps. I used it.   IR (liquid film) ν: 2960, 2800, 1505, 1230 cm^-1．   Dibasic group: 94.1%.   Example 4-1- (p-fluorophenyl) -4- [N- (2- (N '-(p-fluorobenzyl)- N'-Methylamino) ethyl) -N-methylamino] -1-butanone ethylene ketal di Hydrochloride   Same as example 3, but starting material is 1,4-dimethyl-1- (4-fluorobenzyl) The title compound was isolated in a yield of 43.6% using ethylenediamine.   IR (liquid film) ν: 2960, 2805, 1510, 1230 cm^-1．   Dibasic group: 94.7%.   Example 5: 4- [N- (2- (N'-benzyl, N'-methylamino) ethyl) -N-methylami No] -1- (p-fluorophenyl) -1-butanone dihydrochloride   Ethylene ketal (R = H) from Example 3 (38.6 g, 0.1 mol) was mixed with anhydrous ethanol. Dissolve in tanol (300 ml), add 100 ml of 6M hydrochloric acid, and add the mixture to 60 Hold at ~ 70 ° C for 2 hours. This time is not sufficient for TLC to be fully hydrolyzed. So it was proved. The ethanol was then evaporated and the resulting oil was converted to i-PrO. Crystallization in H gave 22.3 g (yield, 54%) of product.   IR (KBr) ν: 3440, 2630, 2480, 1680, 1600, 1 230 cm^-1．   Melting point: 210-215 ° C (decomposition).   Dibasic group: 97.8%.   Elemental analysis C_{twenty one}H₂₇FN₂Analytical value C, 60.56, H, 6. 94, N, 6.52, Cl^-, 16.93; calculated value C, 60.42, H, 7.0. 4, N, 6.74, Cl^-, 17.07.   Example 6: 4- [N- (2- (N'-benzyl, N'-methylamino) ethyl) -N-methylami No] -1- (p-fluorophenyl) -1-butanol dihydrochloride   Ketone obtained in Example 5 (8.3 g, 0.02 mol) and sodium borohydride A mixture of um (1.21 g, 0.032 mol) in absolute ethanol (700 ml). Was reacted at room temperature for 18 hours with stirring. This mixture was mixed with 6M hydrochloric acid in ethanol ( 50 ml), stirred at room temperature for 2 hours and then refluxed for 20 minutes. Solvent Removed in vacuo and treated the resulting residual product with 2M NaOH (200 ml). , Chloroform (3 × 200 ml). The separated organic phase is water (200 m l) washed with anhydrous Na₂SO_FourDried above and concentrated in vacuo. The resin obtained When the product was dissolved in isopropanol and treated with 6M-EtOH-HCl, crystalline Precipitates in the form of a white solid (6.2 g, yield, 74.3%).   IR (KBr) ν: 3400, 2640, 2480, 1520, 1230 cm^-1 ．   Melting point: 208-209 ° C (decomposition).   Dibasic group: 97.9%.   Elemental analysis C_{twenty one}H₂₉FN₂Analytical value C, 60.05, H, 7. 52, N, 6.76, Cl^-, 16.90; calculated value C, 60.43, H, 7.4. 9, N, 6.71, Cl^-, 16.98.   Example 7-1- (p-fluorophenyl) -4- [N- (2- (N '-(p-fluorobenzyl)- N'-Methylamino) ethyl) -N-methylamino] -1-butanone dihydrochloride   Using the corresponding ethylene ketal as the starting material in the same manner as in Example 5, the title A compound is obtained (yield, 83.1%).   IR (KBr) ν: 3440, 2450, 1680, 1600, 1570, 1 240 cm^-1．   Melting point: 227-229 ° C (decomposition).   1 basic group: 98.4%.   Elemental analysis C_{twenty one}H₂₇F₂N₂Analytical value C, 58.03, H, 6. 33, N, 6.38, Cl^-, 16.40; calculated value C, 58.20, H, 6.5. 1, N, 6.46, Cl^-, 16.36.   Example 8-1- (p-fluorophenyl) -4- [N- (2- (N '-(p-fluorobenzyl)- N'-Methylamino) ethyl) -N-methylamino] -1-butanol dihydrochloride   The title compound was obtained in the same manner as in Example 6 using the corresponding ketone as the starting material. (Yield, 87.9%).   IR (KBr) ν: 3440, 2640, 2480, 1520, 1230 cm^-1 ．   Melting point: 218-222 ° C.   Dibasic group: 99.9%.   Elemental analysis C_{twenty one}H₂₈F₂N₂Analytical value C, 57.36, H, 6. 77, N, 6.20, Cl^-, 15.92; calculated value C, 57.93, H, 6.9. 5, N, 6.43, Cl^-, 16.20.   Example 9: N- (4,4-bis (p-fluorophenyl) butyl) -N, N'-dimethyl-N ' -(p-Fluorobenzyl) -1,2-ethanediamine dihydrochloride   Compound of Example 2 (19.6 g, 0.1 mol), 1,1 '-(4-chloro-butylidene) Bis (4-fluorobenzene) (3.65 g, 0.13 mol), anhydrous K₂CO₃(4 1.4 g, 0.3 mol) and a catalytic amount of KI in acetonitrile (400 ml) The mixture was refluxed for 18 hours with stirring. The reaction is TLC (silica gel F₂₅₄, Cl₃ CH / MeOH 9: 1) was used for monitor linking. The reaction liquid is filtered and the solvent is evaporated. I made it. The obtained oily substance was subjected to flash chromatography (silica gel, Cl₃ Purified by CH / MeOH 9: 1) and dissolved in ethanol-hydrochloric acid under heating Crystallized as the dihydrochloride salt. 35.3 g of a crystalline white product (yield, 68. 8%) was obtained.   IR (KBr) ν: 3440, 2925, 1510, 1240 cm^-1．   Melting point: 203-206 ° C.   Dibasic group: 99.4%.   Elemental analysis C₂₇H₃₁F₃N₂-Analysis value C, 63.07, H, 6.4 as 2HCl 7, N, 5.34, Cl^-, 13.72; calculated value C, 63.16, H, 6.48. , N, 5.46, Cl^-, 13.81.   Example 10: 1,4-dimethyl-1- (2-pyrimidinyl) ethylenediamine   N, N'-dimethylethylenediamine (88.15 g, 1 mol), 2-chloropyro Limidine (114.5 g, 1 mol), NaHCO₃(252g, 3mol) Eta The mixture was stirred in nol (1 L) and heated at reflux for 24 hours. Leave the solution Bring to an appropriate temperature, then filter to remove inorganic salts and use rotavapor to remove solvent. Was evaporated. The oily liquid was dissolved in 500 ml of 1M hydrochloric acid and chloroform ( 2 × 250 ml) and extracted twice. The aqueous phase is made basic and chloroform (3 x 2 It was extracted 3 times with 50 ml). Combine the organic fractions and dry Na₂SO_FourDried on the solvent Evaporate the to give 54 g of a pure, bright oil by chromatography (yield: Rate, 32.5%) was obtained, which was directly used in the following steps.   IR (liquid film) ν: 3320, 2940, 1590, 1410, 1390 cm^-1 ．   Dibasic group: 99.1%.   Example 11-1- (p-fluorophenyl) -4- [N- [2- (N '-(2-pyrimidinyl) -N] '-Methyl-amino) ethyl] -N-methylamino] -1-butanone ethyleneketane di-salt Acid salt   The compound of Example 10 (16.6 g, 0.1 mol) in 300 m of acetonitrile γ-chloro-p-fluorobutyrophenone ethylene ketal (29. 4 g, 0.12 mol), anhydrous K₂CO₃(41.4 g, 0.3 mol) and catalytic amount KI was sequentially added. The mixture was refluxed for 24 hours. The progress of the reaction is silica Gel F₂₅₄Chromatography using chloroform-methanol (8: 2) as eluent. It was monitored by topography. The reaction mixture is left to reach the proper temperature and the organic salt Was filtered and the solvent was evaporated to give 42.6 g of crude product. Followed by this Column chromatography (silica gel: eluent Cl₃CH and Cl₃CH / M Purified by eOH 95: 5). Chromatographically pure product 17. 7 g (yield, 47.3%) were obtained in the form of an oil.   IR (liquid film) ν: 2940, 1590, 1410, 1390, 1230 cm^-1   Example 12-1- (p-fluorophenyl) -4- [N- (2- (N '-(2-pyrimidinyl) -N' -Methyl-amino) ethyl) -N-methylamino] -1-butanone disulfate   The compound of Example 11 (18.7 g, 0.5 mol) was added to absolute ethanol (150 ml). 20 ml of 6M hydrochloric acid was added and the mixture was kept at 60-70 ° C for 2 hours. (Progress of hydrolysis was monitored by TLC). Then steam ethanol After evaporating to dryness, the obtained crude product was dissolved in water (50 ml), and the residue was washed with 2M NaOH. It was rendered rucal and extracted with chloroform (2 x 50 ml). Combine the organic phases, Anhydrous Na₂SO_FourDried above, filtered and evaporated to dryness. 100 m of the produced oily substance When dissolved in 1 L of acetone and acidified with 2M sulfuric acid, it was chromatographically pure. 8.2 g (yield, 31.2%) of the desired product were obtained in the form of a crystalline white solid.   IR (KBr) ν: 3440, 2960, 1690, 1630, 1220 cm^-1 ．   Melting point: 208-212 ° C.   Elemental analysis C₁₈H_{twenty three}FN_FourO · 2H₂SO_FourAnalysis value C, 41.11, H, 5 ． 10, N, 10.79, S, 11.93; calculated value C, 41.06, H, 5.1. 3, N, 10.60, S, 12.18.   Example 131- (p-fluorophenyl) -4- [N- (2- (N '-(2-pyrimidini ) -N'-Methyl-amino) ethyl) -N-methylamino] -1-butanol disulfate salt   Compound of Example 12 (10.52 g, 0.02 mol) and sodium borohydride A mixture of sodium chloride (1.51 g, 0.04 mol) in absolute ethanol (250 ml). The reaction was allowed to stir at warm temperature for 24 hours. This mixture was mixed with 6M hydrochloric acid in ethanol (50m l) and refluxed for 30 minutes. The solvent was removed in vacuo and the resulting residue was Treat with 2M-NaOH (200 ml) and extract with chloroform (3 x 200 ml). I put it out. The organic phases are combined and washed with water (200 ml), anhydrous Na₂SO_FourDried on And concentrated in vacuo. The resinous material thus obtained was dissolved in acetone. , Treated with sulfuric acid. 2 g (18 g) of a chromatographically pure crystalline white solid ． 9%) was precipitated.   IR (KBr) ν: 3420, 2960, 1690, 1640, 1520, 1 220 cm^-1．   Melting point: 179-181 ° C.   Elemental analysis C₁₈H_{twenty five}FN_FourO · 2H₂SO_FourAnalysis value C, 40.68, H, 5 ． 35, N, 10.47, S, 12.15; calculated value C, 40.90, H, 5.5. 3, N, 10.60, S, 12.12.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI C07D 239/42 Z 8615-4C // C07D 319/08 9454-4C (72) Inventor Ortiz, Jose Spain EES ― 08037 Barcelona, A. Corsega 429 (72) Inventor Sacristan, Olério Spain Ees 08034 Barcelona, Santa Amelia 2 (72) Inventor Castello, Josep Em. Spain Ees 08012 Barcelona, Plance das Turies 35

Claims (1)

[Claims] 1. General formula (I): [Wherein X is a carbonyl (CO), hydroxymethylene (CHOH) or p-fluorophenyl-methylene (p-F-C ₆ H ₄ -CH) group, and R is a p-position substituted with halogen. Optionally a benzyl group, or R is a 2-pyrimidinyl group. However, at the same time, X is not p-fluorophenyl-methylene (p-F-C ₆ H ₄ -CH) and R is not an unsubstituted benzyl group] N, N, N ', N'-tetra-substituted- 1,2-ethanediamine compounds, and pharmaceutically acceptable addition salts thereof. The halogen optionally substituting the p-position of the benzyl group is fluorine, wherein the compound is 3.1- (p-fluorophenyl) -4- [N- (2- (N'- 3. (p-Fluorobenzyl) -N'-methylamino) ethyl) -N-methylamino] -1-butanone and especially its dihydrochloride salt according to claim 1 and 4. 4. A method for treating a sigma receptor-related nervous system disease, which comprises administering a compound of general formula (I). 5. A pharmaceutical composition comprising at least one compound according to claim 1 optionally in combination with a pharmaceutically acceptable carrier and / or auxiliary agent. In preparing the compound of formula I according to claims 1 to 3, the compound of formula III: (Wherein R is as defined in claim 1), the compound of formula IVa: Reacting with a compound of the formula V, where Z is a suitable leaving group, And the compound of formula V is subjected to acetal hydrolysis to give a compound of formula I where X is carbonyl, and then optionally the carbonyl group is reduced to the corresponding alcohol group to yield X of formula I Or a compound of formula (III) above is obtained by formula (IVb) A compound of formula I wherein x is p-F-C ₆ H ₄ -CH by reaction with X is p-F-C ₆ H ₄ -CH and Z is a suitable leaving group. And a method of converting the compound of formula I thus obtained, if desired, into a pharmaceutically acceptable addition salt